Inhibition Of Fibroblast Growth Factor Research Articles

Adipose Stromal Cell-Derived Cancer-Associated Fibroblasts Suppress FGFR Inhibitor Efficacy.

Cancer aggressiveness has been linked with obesity, and studies have shown that adipose tissue can enhance cancer progression. In this issue of Cancer Research, Hosni and colleagues discover a paracrine mechanism mediated by adipocyte precursor cells through which urothelial carcinomas become resistant to erdafitinib, a recently approved therapy inhibiting fibroblast growth factor receptors (FGFR). They identified neuregulin 1 (NRG1) secreted by adipocyte precursor cells as an activator of HER3 signaling that enables resistance. The NRG1-mediated FGFR inhibitor resistance was amenable to intervention with pertuzumab, an antibody blocking the NRG1/HER3 axis. To investigate the nature of the resistance-associated NRG1-expressing cells in human patients, the authors analyzed published single-cell RNA sequencing data and observed that such cells appear in a cluster assigned as inflammatory cancer-associated fibroblasts (iCAF). Notably, the gene signature corresponding to these CAFs is highly similar to that shared by adipose stromal cells (ASC) in fat tissue and fibro-adipogenic progenitors (FAP) in skeletal muscle of cancer-free individuals. Because fibroblasts with the ASC/FAP signature are enriched in various carcinomas, it is possible that the paracrine signaling conferred by NRG1 is a pan-cancer mechanism of FGFR inhibitor resistance and tumor aggressiveness. See related article by Hosni et al., p. 725.

Case report: Pemigatinib-induced retinopathy: a serial examination of subretinal fluid secondary to an FGFR inhibitor

BackgroundModern chemotherapeutic agents continue to evolve as modern monoclonal antibody treatments are designed to directly target proteins, enzymes, and focal loci. A particular class of these medications, fibroblast growth factor (FGFR) inhibitors, specifically pemigatinib (Pemazyre®; Incyte), has been approved by the US Food and Drug Administration since April 2020 for the treatment of advanced or metastatic cholangiocarcinoma. As it is a relatively new medication, its side-effect profile is manifesting in active clinical practice. The presence of FGFR receptors in the retinal pigment epithelium makes the retina susceptible to potential adverse effects secondary to pemigatinib use.Case presentationA 69-year-old African-American male with a tumor mutation burden 3 (TMB-3) metastatic adenocarcinoma of the liver from primary cholangiocarcinoma, who was undergoing chemotherapy with pemigatinib, was found to have asymptomatic bilateral subretinal fluid accumulation. Serial monitoring with optical coherence tomography (OCT) demonstrated complete resolution of the subretinal fluid while off-cycle and asymptomatic re-accumulation of subretinal fluid while on-cycle, with no significant changes in visual acuity.ConclusionsSubretinal fluid accumulation secondary to pemigatinib may develop during the active treatment cycles without causing any significant visual symptoms for the patient. Serial monitoring demonstrates fluctuations of subretinal fluid during the patient’s on- and off-cycles. This case strengthens the current guidelines for continuing pemigatinib in asymptomatic patients found to have subretinal fluid. Further studies are warranted to identify patients who may be at higher risk for developing subretinal fluid.

First-308: Phase III study of tinengotinib versus physician's choice in patients with FGFR-altered, chemotherapy- and FGFR inhibitor–refractory/relapsed cholangiocarcinoma.

TPS575 Background: Fibroblast growth factor (FGFR) alterations occur in 10-15% of adult patients with advanced intrahepatic cholangiocarcinoma (CCA) and 1-2% of adult patients with advanced extrahepatic cholangiocarcinoma. The first generation FGFR inhibitors (FGFRi) pemigatinib and futibatinib, have been approved for the treatment of advanced CCA with FGFR2 fusions or rearrangements after systemic chemotherapy. However, disease progression occurs within 6-9 months. Secondary polyclonal mutations in the FGFR kinase domain represent a prominent acquired resistance mechanism. Tinengotinib, a novel multi-kinase inhibitor with high potency against a variety of FGFR2 kinase domain mutations, has shown promising clinical benefit in subjects with FGFR-altered metastatic CCA who were heavily pretreated with chemotherapy and FGFRi(s) in phase I/II clinical trials. (NCT03654547, NCT04742959, NCT04919642). Methods: FIRST-308 is a phase III, randomized, global multicenter study to evaluate the efficacy and safety of oral tinengotinib versus Physician’s Choice in subjects with FGFR-altered, chemotherapy- and FGFRi-refractory/relapsed CCA. Approximately 200 subjects will be enrolled in US, Europe, and Asia. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0 or 1, documentation of FGFR2 fusion/rearrangement gene status, prior treatment with at least one line of chemotherapy and exactly one prior FDA-approved FGFRi for unresectable or metastatic disease. The study includes Part A and Part B. The Part A is to select a dose for Part B. Eligible subjects will be randomized in a 2:2:1 ratio to receive tinengotinib 8 mg QD, tinengotinib 10 mg QD or Physician's Choice (FOLFOX or FOLFIRI) in Part A or 2:1 in Part B to receive the recommended Part B dose or Physician's Choice. The stratification factors at randomization include geographic region, prior lines of chemotherapy (1 or ≥ 2) and Physician’s choice. Tinengotinib will be administered orally QD in 28-day cycles. Subjects will continue to receive study treatment until confirmed disease progression, unacceptable toxicity, withdrawal of consent, or termination of study by Sponsor, whichever occurs first. For Part A, the primary endpoint is safety/tolerability; secondary endpoints include objective response rate (ORR), duration of response (DOR) and PK analysis. For Part B, the primary endpoint is progression-free survival (PFS); secondary endpoints include overall survival (OS), ORR, DOR, safety, quality of life and population PK. Exploratory endpoints will assess the correlations between baseline FGFR2 alterations by cfDNA and efficacy, and exposure-response in terms of efficacy and safety. Study is open for enrollment. Clinical trial information: NCT05948475 .

Efficacy and safety of nintedanib in patients with non-small cell lung cancer, and novel insights in radiation-induced lung toxicity.

Nintedanib is a tyrosine kinase inhibitor of fibroblast growth factor-, vascular endothelial growth factor-, and platelet-derived growth factor receptors. These three receptors promote new blood vessel formation and maintenance, which is essential for tumor growth and spread. Several trials have shown that nintedanib plays a substantial role in treating patients with non-small cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis. Recently, several clinical trials of nintedanib to treat NSCLC have been reported. In this review, we focus on our current understanding of nintedanib treatment for advanced NSCLC patients and summarize the literature on using nintedanib in radiation-induced lung toxicity and the efficacy and tolerability of nintedanib.

Lysimachia christinae polysaccharide attenuates diet-induced hyperlipidemia via modulating gut microbes-mediated FXR–FGF15 signaling pathway

Polysaccharides are one of the most abundant and active components of Lysimachia christinae (L. christinae), which is widely adopted for attenuating abnormal cholesterol metabolism; however, its mechanism of action remains unclear. Therefore, we fed a natural polysaccharide (NP) purified from L. christinae to high-fat diet mice. These mice showed an altered gut microbiota and bile acid pool, which was characterized by significantly increased Lactobacillus murinus and unconjugated bile acids in the ileum. Oral administration of the NP reduced cholesterol and triglyceride levels and enhanced bile acid synthesis via cholesterol 7α-hydroxylase. Additionally, the effects of NP are microbiota-dependent, which was reconfirmed by fecal microbiota transplantation (FMT). Altered gut microbiota reshaped bile acid metabolism by modulating bile salt hydrolase (BSH) activity. Therefore, bsh genes were genetically engineered into Brevibacillus choshinensis, which was gavaged into mice to verify BSH function in vivo. Finally, adeno-associated-virus-2-mediated overexpression or inhibition of fibroblast growth factor 15 (FGF15) was used to explore the farnesoid X receptor–fibroblast growth factor 15 pathway in hyperlipidemic mice. We identified that the NP relieves hyperlipidemia by altering the gut microbiota, which is accompanied by the active conversion of cholesterol to bile acids.

Futibatinib (Lytgobi®)

Futibatinib (Lytgobi®)

Acellular biomaterial modulates myocardial inflammation and promotes endogenous mechanisms of postinfarct cardiac repair.

After myocardial infarction, we previously showed that epicardial implantation of porcine small intestinal submucosal extracellular matrix (SIS-ECM) improves postinfarct cardiac function through fibroblast-mediated angiogenic and antifibrotic pathways. Herein, we characterize how SIS-ECM also coordinates a reparative cardiac inflammatory response. RNA sequencing and multiplex characterized modulation of fibroblast transcriptional and paracrine activity by SIS-ECM. Inhibitors of fibroblast growth factor 2 and toll-like receptor 9 elucidated mechanism. Mice received coronary ligation (infarction) and either SIS-ECM implantation (treatment) or sham surgery (control). Flow cytometry of SIS-ECM and the murine myocardium quantified monocytes, neutrophils, and proangiogenic subtypes. Microscopy tracked fibroblasts and immune cells, and characterized myocardial angiogenesis. SIS-ECM increased fibroblast transcription of inflammatory pathways and production of angiogenic vascular endothelial growth factor and inflammatory cytokines via fibroblast growth factor 2 and toll-like receptor 9-dependent pathways. Two-photon microscopy showed that SIS-ECM became engrafted by native fibroblasts and leukocytes, subsequently increasing release of inflammatory cytokines and angiogenic vascular endothelial growth factor. On flow cytometry, SIS-ECM implantation increased day-7 myocardial counts of neutrophils, inflammatory monocytes, and proangiogenic vascular endothelial growth factor recptor 1 subtypes. SIS-ECM has a higher proportion of proangiogenic leukocytes compared with the myocardium. Resonant confocal microscopy showed neovascularization near SIS-ECM. SIS-ECM promotes engraftment by native fibroblasts and leukocytes, and modulates fibroblast activity via fibroblast growth factor 2 and toll-like receptor 9 to potentiate a proangiogenic inflammatory response. Subsequently, the material increases myocardial counts of reparative proangiogenic leukocytes that can induce neovascularization. This reparative inflammatory response may explain previously reported functional improvements. Fibroblast growth factor 2 and toll-like receptor 9 mechanisms can be leveraged to design next-generation materials for postinfarct cardiac repair.

Tumor and Stromal Cell Targeting with Nintedanib and Alpelisib Overcomes Intrinsic Bladder Cancer Resistance.

Bladder cancer is a highly prevalent tumor, requiring the urgent development of novel therapies, especially for locally advanced and metastatic disease. Nintedanib is a potent antifibrotic angio-kinase inhibitor, which has shown clinical efficacy in combination with chemotherapy in patients with locally advanced muscle-invasive bladder cancer. Nintedanib inhibits fibroblast growth factor receptors (FGFRs), validated targets in patients with bladder cancer harboring FGFR3/2 genetic alterations. Here, we aimed at studying its mechanisms of action to understand therapy resistance, identify markers predictive of response, and improve the design of future clinical trials. We have used a panel of genetically well-characterized human bladder cancer cells to identify the molecular and transcriptomic changes induced upon treatment with nintedanib, in vitro and in vivo, at the tumor and stroma cell levels. We showed that bladder cancer cells display an intrinsic resistance to nintedanib treatment in vitro, independently of their FGFR3 status. However, nintedanib has higher antitumor activity on mouse xenografts. We have identified PI3K activation as a resistance mechanism against nintedanib in bladder cancer and evidenced that the combination of nintedanib with the PI3K inhibitor alpelisib has synergistic antitumor activity. Treatment with this combination is associated with cell-cycle inhibition at the tumoral and stromal levels and potent nontumor cell autonomous effects on α-smooth muscle actin-positive tumor infiltrating cells and tumor vasculature. The combination of nintedanib with PI3K inhibitors not only reversed bladder cancer resistance to nintedanib but also enhanced its antiangiogenic effects.

Management of Fibroblast Growth Factor Inhibitor Treatment–emergent Adverse Events of Interest in Patients with Locally Advanced or Metastatic Urothelial Carcinoma

BackgroundErdafitinib is indicated for the treatment of adults with locally advanced/metastatic urothelial carcinoma and susceptible FGFR3/2 alterations progressing on/after one or more lines of prior platinum-based chemotherapy. ObjectiveTo better understand the frequency and management of select treatment-emergent adverse events (TEAEs) to enable optimal fibroblast growth factor receptor inhibitor (FGFRi) treatment. Design, setting, and participantsLonger-term efficacy and safety results of the BLC2001 (NCT02365597) trial in patients with locally advanced and unresectable or metastatic urothelial carcinoma were studied. InterventionErdafitinib schedule of 8 mg/d continuous in 28-d cycles, with uptitration to 9 mg/d if serum phosphate level was <5.5 mg/dl and no significant TEAEs occurred. Outcome measurements and statistical analysisAdverse events were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The Kaplan-Meier methodology was used for the cumulative incidence of the first onset of TEAEs by grade. Time to resolution of TEAEs was summarized descriptively. Results and limitationsAt data cutoff, the median treatment duration was 5.4 mo among 101 patients receiving erdafitinib. Select TEAEs (total; grade 3) were hyperphosphatemia (78%; 2.0%), stomatitis (59%; 14%), nail events (59%; 15%), non–central serous retinopathy (non-CSR) eye disorders (56%; 5.0%), skin events (55%; 7.9%), diarrhea (55%; 4.0%), and CSR (27%; 4.0%). Select TEAEs were mostly of grade 1 or 2, and were managed effectively with dose modifications, including dose reductions or interruptions, and/or supportive concomitant therapies, resulting in few events leading to treatment discontinuation. Further work is needed to determine whether management is generalizable to the nonprotocol/general population. ConclusionsIdentification of select TEAEs and appropriate management with dose modification and/or concomitant therapies resulted in improvement or resolution of most TEAEs in patients, allowing for continuation of FGFRi treatment to ensure maximum benefit. Patient summaryEarly identification and proactive management are warranted to mitigate or possibly prevent erdafitinib side effects to allow for maximum drug benefit in patients with locally advanced or metastatic bladder cancer.

HDAC1 overexpression promoted by METTL3-IGF2BP2 inhibits FGF21 expression in metabolic syndrome-related liver injury.

Metabolic syndrome (MetS) represents a cluster of diseases that includes diabetes and insulin resistance. A combination of these metabolic disorders damages liver function. We hypothesized here that histone deacetylase 1 (HDAC1) inhibits fibroblast growth factor 21 (FGF21) expression through histone deacetylation, thereby accentuating liver injury in rats with MetS. MetS rats induced by a high-fat diet were monitored weekly for blood pressure and body weight measurement. The changes of hepatic injury parameters were also measured. The pathological changes in the liver were observed by HE staining and oil red O staining. We found that HDAC1 was increased in the liver of rats with MetS, while sh-HDAC1 reduced blood pressure, body weight, and hepatic injury parameters. Improvement of structural pathological alterations and reduction of lipid deposition were observed after HDAC1 inhibition. Notably, HDAC1 inhibited FGF21 expression through histone deacetylation. The hepatoprotective effects of sh-HDAC1 on rats were reversed by adenovirus-mediated knockdown of FGF21. Moreover, methyltransferase-like 3 (METTL3) mediated the N6-methyladenosine (m6A) modification of HDAC1 mRNA and increased its binding to IGF2BP2. Consistently, sh-METTL3 inhibited HDAC1 and increased FGF21 expression, thereby ameliorating liver injury in MetS rats. This study discovered that HDAC1 is capable of managing liver injury in MetS. Targeting HDAC1 may be an optimal treatment for MetS-related liver injury.

AZD4547 and the Alleviation of Hepatoma Cell Sorafenib Resistance via the Promotion of Autophagy.

This study is part of a larger research effort to explore the molecular mechanism of hepatocellular carcinoma, reduce drug resistance and seek new targets. The objective of this study is to investigate the effect and mechanism of fibroblast growth factor receptor inhibitor AZD4547 on Sorafenib-resistant hepatoma cells. First, we constructed a Sorafenib-resistant hepatoma cell line Huh7R. Different groups of Huh7R cells were treated with Sorafenib, AZD4547, Sorafenib combined with AZD4547, and normal saline. The cell viability was detected by Cell Counting Kit-8. Then Fibroblast growth factor receptor and Toll-like receptor 4 were detected by Western blot, as well as the LC3 II/I, Beclin1, and P62. In addition, we used the autophagy inhibitor 3-methyladenine to identify the mechanism of AZD4547 combined with Sorafenib for inducing Sorafenib-resistant hepatoma cell death. We find that AZD4547 combined with Sorafenib significantly inhibited the viability of Sorafenib-resistant hepatoma cell Huh7R. As for its mechanism, AZD4547 was able to inhibit fibroblast growth factor receptor activity, promote autophagy and regulate immunity. AZD4547 increased LC3 II/I, Beclin1, and Toll-like receptor 4 proteins, and decreased P62 protein level in Huh7R cells significantly when given in combination with sorafenib. Furthermore, 3-methyladenine inhibited autophagy and reversed the killing effect of the combination of AZD4547 and Sorafenib on Huh7R cells. The inhibition of fibroblast growth factor receptor activity by AZD4547 can significantly enhance autophagy and immune response, as well as promote the death of Sorafenib-resistant hepatoma cells.

Cucurbitacin promotes hair growth in mice by inhibiting the expression of fibroblast growth factor 18.

The inhibition of fibroblast growth factor 18 (FGF18) promotes the transition of hair follicles (HFs) from the telogen phase to the anagen phase. Cucurbitacin has been shown to have a good effect in promoting hair cell growth. This study explored the potential effect of cucurbitacin on hair growth and its effect on FGF18 expression in mice. Male C57BL/6J mice were randomly divided into the following two groups: (I) the vehicle group; and (II) the cucurbitacin group. Matrix cream and cucurbitacin cream were applied to the depilated skin on the back of the vehicle group mice and the cucurbitacin group mice, respectively. On days 3, 6, 9, 12, 15, and 18, the hair growth in the depilated dorsal skin of the mice was recorded with a digital camera and a HF detector, and the HF cycle status of the mice was observed by hematoxylin and eosin (H&E) staining. In addition, the level of FGF18 messenger ribonucleic acid (mRNA) in the dorsal skin was measured on days 15 and 18 by quantitative real-time polymerase chain reaction (qRT-PCR), while the level of FGF18 protein was measured by western blot and immunofluorescence staining. The dorsal skin to which the cucurbitacin cream was applied began to darken on day 6 and grew hairs on day 9, which was 3 days earlier than the dorsal skin to which the matrix cream was applied. The H&E staining revealed a transition from the telogen phase to the anagen phase 3 days earlier for the cucurbitacin cream-treated skin than the matrix cream-treated skin. In addition, the skin treated with cucurbitacin cream also showed a significant decrease in FGF18 mRNA as seen by qRT-PCR, and reduced FGF18 protein levels as detected by western blot and immunofluorescence staining compared to the skin treated with matrix cream only. Cucurbitacin significantly reduced the levels of FGF18 mRNA and protein in the dorsal skin of mice to accelerate the HFs to enter the anagen phase earlier, thereby promoting the regeneration of hair. Thus, cucurbitacin can be considered a new and valuable agent for the development of anti-hair loss products.

TTYH3 Modulates Bladder Cancer Proliferation and Metastasis via FGFR1/H-Ras/A-Raf/MEK/ERK Pathway

Tweety family member 3 (TTYH3) is a calcium-activated chloride channel with a non-pore-forming structure that controls cell volume and signal transduction. We investigated the role of TTYH3 as a cancer-promoting factor in bladder cancer. The mRNA expression of TTYH3 in bladder cancer patients was investigated using various bioinformatics databases. The results demonstrated that the increasingly greater expression of TTYH3 increasingly worsened the prognosis of patients with bladder cancer. TTYH3 knockdown bladder cancer cell lines were constructed by their various cancer properties measured. TTYH3 knockdown significantly reduced cell proliferation and sphere formation. Cell migration and invasion were also significantly reduced in knockdown bladder cancer cells, compared to normal bladder cancer cells. The knockdown of TTYH3 led to the downregulation of H-Ras/A-Raf/MEK/ERK signaling by inhibiting fibroblast growth factor receptor 1 (FGFR1) phosphorylation. This signaling pathway also attenuated the expression of c-Jun and c-Fos. The findings implicate TTYH3 as a potential factor regulating the properties of bladder cancer and as a therapeutic target.

Role of Calcimimetics in Treating Bone and Mineral Disorders Related to Chronic Kidney Disease.

Renal osteodystrophy is common in patients with chronic kidney disease and end-stage renal disease and leads to the risks of fracture and extraosseous vascular calcification. Secondary hyperparathyroidism (SHPT) is characterized by a compensatory increase in parathyroid hormone (PTH) secretion in response to decreased renal phosphate excretion, resulting in potentiating bone resorption and decreased bone quantity and quality. Calcium-sensing receptors (CaSRs) are group C G-proteins and negatively regulate the parathyroid glands through (1) increasing CaSR insertion within the plasma membrane, (2) increasing 1,25-dihydroxy vitamin D3 within the kidney and parathyroid glands, (3) inhibiting fibroblast growth factor 23 (FGF23) in osteocytes, and (4) attenuating intestinal calcium absorption through Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6). Calcimimetics (CaMs) decrease PTH concentrations without elevating the serum calcium levels or extraosseous calcification through direct interaction with cell membrane CaSRs. CaMs reduce osteoclast activity by reducing stress-induced oxidative autophagy and improving Wnt-10b release, which promotes the growth of osteoblasts and subsequent mineralization. CaMs also directly promote osteoblast proliferation and survival. Consequently, bone quality may improve due to decreased bone resorption and improved bone formation. CaMs modulate cardiovascular fibrosis, calcification, and renal fibrosis through different mechanisms. Therefore, CaMs assist in treating SHPT. This narrative review focuses on the role of CaMs in renal osteodystrophy, including their mechanisms and clinical efficacy.

Natural fish oil improves the differentiation and maturation of oligodendrocyte precursor cells to oligodendrocytes in vitro after interaction with the blood–brain barrier

The blood–brain barrier (BBB) tightly controls the microenvironment of the central nervous system (CNS) to allow neurons to function properly. Additionally, emerging studies point to the beneficial effect of natural oils affecting a wide variety of physiological and pathological processes in the human body. In this study, using an in vitro model of the BBB, we tested the influence of natural fish oil mixture (FOM) vs. borage oil (BO), both rich in long-chain polyunsaturated fatty acids (LC-PUFAs) and monounsaturated fatty acids (MUFAs) such as oleic acid (C18:1n9c) or nervonic acid (NA), on human oligodendrocyte precursor cells (hOPCs) during their maturation to oligodendrocytes (OLs) regarding their ability to synthesize myelin peptides and NA. We demonstrated that FOM, opposite to BO, supplemented endothelial cells (ECs) and astrocytes forming the BBB, affecting the function of hOPCs during their maturation. This resulted in improved synthesis of myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), proteolipid protein (PLP), and NA in mature OLs. This effect is probably the result of BBB cell and hOPC stimulation via free fatty acid receptors (FFARs), which increases insulin growth factor-1 (IGF-1), ciliary neurotrophic factor (CNTF), and brain-derived neurotrophic factor (BDNF) and inhibits fibroblast growth factor 2 (FGF-2) synthesis. The unique formula of fish oil, characterized by much more varied components compared to those of BOs, also improved the enhancement of the tight junction by increasing the expression of claudin-5 and VE-cadherin on ECs. The obtained data justify consideration of naturally derived fish oil intake in human diet as affecting during remyelination.

Fibroblast Growth Factor 3 Is Associated with Tongue Squamous Cell Carcinoma: A Controlled Study.

Objective To explore the effects of fibroblast growth factor 3 (FGF3) on the proliferation, cell cycle, and apoptosis of the tongue squamous cell carcinoma SCC-9 cell line (SCC-9). Methods We measured the proliferation of SCC-9 cells in a control group, an FGF3 intervention group, and a fibroblast growth factor (FGFR) inhibitor intervention group in cholecystokinin octapeptide (CCK-8) experiments. We studied effects of FGF3 on the cell cycle and apoptosis of tongue cancer cells using flow cytometry. We further explored the IRS1/PI3K/AKT signaling pathway by measuring BCL-2 and Bcl-2 Associated X-protein (BAX) mRNA and protein levels with RT-PCR and western blot, respectively. Results Results from the CCK-8 experiment showed that survival rates of cells in the control group, FGF3 intervention group, and FGFR inhibitor intervention group were 100.000% ± 4.026%, 136.330% ± 9.779%, and 83.199% ± 4.954%, respectively; survival rates of SCC-9 cells in all three groups were statistically significant (P < 0.05). Compared with that in the control group, the ratio of cells in G0/G1 phase in the FGFR inhibitor intervention group was higher (P < 0.05) and that in G2/M phase was lower, while the FGF3 intervention group showed opposite results (P < 0.05). The apoptosis rate of tongue cancer cells differed significantly between the FGFR inhibitor intervention and the control groups (P < 0.05). The mRNA and protein expression levels of IRS1, PI3K, and BCL-2 were all increased in the FGF3 intervention group (P < 0.05), while BAX mRNA and protein expression levels were decreased (P < 0.05). The mRNA expression levels of protein kinase B (AKT) showed no differences between groups. The p-AKT protein was overexpressed, while the total amount of AKT protein remained stable (P < 0.05). Conclusion FGF3 contributes to the proliferation of SCC-9 cells by increasing the proportion of cells in G2/M phase. Therefore, appropriately timed inhibition of FGF3 can potentially promote tumor apoptosis through the IRS1/PI3K/AKT signaling pathway. Our results demonstrate the role of FGF3 in the tumor microenvironment in tongue squamous cell carcinoma SCC-9 cells and suggest new therapeutic targets.

P-77 A phase II study of multiple kinase inhibitor, TT-00420, in advanced, refractory cholangiocarcinoma

Fibroblast growth factor (FGFR) alterations occur in 10-15% adult patients with advanced cholangiocarcinoma (CCA). Pemigatinib and Infigratinib, the first generation FGFR1-3 kinase inhibitors approved for the treatment of the advanced CCA with FGFR2 gene fusions or other rearrangements, are associated with a median progression-free survival of about 6 months after progression on first-line chemotherapy and acquired resistance is common. A novel spectrum-selective multi-kinase inhibitor, TT-00420, has shown clinical responses in multiple CCA patients bearing the gate-keeper mutations acquired from previous FGFR inhibitor treatment(s) in prior phase I study (NCT03654547).

Fibroblast Growth Factor Inhibitors for Treating Locally Advanced/Metastatic Bladder Urothelial Carcinomas via Dual Targeting of Tumor-Specific Oncogenic Signaling and the Tumor Immune Microenvironment.

Locally advanced or metastatic urothelial bladder cancer (a/m UBC) is currently treated using platinum-based combination chemotherapy. Immune checkpoint inhibitors (ICIs) are the preferred second-line treatment options for cisplatin-eligible a/m UBC patients and as first-line options in cisplatin-ineligible settings. However, the response rates for ICI monotherapy are modest (~20%), which necessitates the exploration of alternative strategies. Dysregulated activation of fibroblast growth factor receptor (FGFR) signaling enhances tumor proliferation, survival, invasion, angiogenesis, and immune evasion. The recent U.S. Food and Drug Administration approval of erdafitinib and the emergence of other potent and selective FGFR inhibitors (FGFRis) have shifted the treatment paradigm for patients with a/m UBC harboring actionable FGFR2 or FGFR3 genomic alterations, who often have a minimal-to-modest response to ICIs. FGFRi–ICI combinations are therefore worth exploring, and their preliminary response rates and safety profiles are promising. In the present review, we summarize the impact of altered FGFR signaling on a/m UBC tumor evolution, the clinical development of FGFRis, the rationale for FGFRi–ICI combinations, current trials, and prospective research directions.

711P Outcomes according to genomic characteristics of patients with metastatic urothelial carcinoma in phase I/II trials

Metastatic urothelial carcinoma (mUC) is an aggressive disease with few available therapeutics until recent approval of immune checkpoint inhibitors (ICI), fibroblast growth factor inhibitor receptor inhibitors and antibody-drug conjugate. Nevertheless, some patients do not respond to these treatments and predictive biomarkers are needed, especially for ICI.

Abstract CT173: Sunitinib (S) in patients (pts) with metastatic breast cancer (mBC) with FGFR1 mutations or amplifications: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study

Abstract Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. S is an oral multi-kinase inhibitor that inhibits Fibroblast Growth Factor Receptor family members 1-4 (FGFR1-4) in biochemical and cellular assays and is FDA approved in several tumor types. Results in a cohort of mBC pts with FGFR1 mutations (mut) or amplifications (amp) treated with S are reported. Methods: Eligible pts had mBC, no standard treatment (tx) options, measurable disease, ECOG Performance Status (PS) 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received S 50 mg orally daily for four weeks followed by two weeks off, until tumor progression. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Thirty pts with mBC with FGFR1 mut (1 pt), amp (28 pts), or both (1 pt) were enrolled from Oct 2016 to June 2019. 3 were not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table 1. Two partial responses (PR) and 5 SD16+ (FGFR1 amp only) were observed for DC and OR rates of 29% (95% CI: 13%, 42%) and 7% (95% CI: 1%, 24%), respectively, and the null DC rate of 15% was rejected (p=0.09). S related grade 3-5 TAEs (Table 1) were consistent with the product label for S except encephalopathy. Conclusions: Monotherapy S showed modest anti-tumor activity and clinically significant TAEs in heavily pre-treated pts with mBC with FGFR1 amplification. Table 1.Demographics, Efficacy (N=27) and Toxicity Outcomes (N=30)Median age, yrs (range)61 (28, 81)Female, %97ECOG PS, %047137217Prior systemic regimens, %1-210≥390Hormone Receptor (HR) &amp; HER2 Status, %HR (+) HER2 (-)77HR (-) HER2(-)13HR (+) HER2 (+)7Not reported3DC rate, % (OR or SD16+) (95% CI)29 (13, 42)OR rate, % (95% CI)7 (1, 24)Median PFS, wks (95% CI)8.7 (8.1, 15.7)Median OS, wks (95% CI)33.9 (23.0, 49.0)Number of Pts with Treatment-related AEs/SAEs (TAEs, maximum grade reported)Grade 211Grade 329Grade 4321Skin infection (SAE)2Cytopenia, encephalopathy (SAE), febrile neutropenia (SAE), increased alkaline phosphatase, Palmar-plantar erythrodysesthesia syndrome, vomiting3Cytopenia, hypertension Citation Format: Carmen Calfa, Michael Rothe, Pam K. Mangat, Elizabeth Garrett-Mayer, Eugene Ahn, Keerthi Gogineni, Nitin Rohatgi, Monika L. Burness, Anu Gaba, Omid Hamid, Tareq Albaghdadi, Alison Conlin, Philip Gold, Jordi Rodon, Ramya Thota, Richard L. Schilsky. Sunitinib (S) in patients (pts) with metastatic breast cancer (mBC) with FGFR1 mutations or amplifications: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT173.